SK8812000A3 - Substituted amidino compounds in the treatment of chronic obstructive pulmonary disease - Google Patents

Abstract

Use in medicaments for the treatment of chronic obstructive pulmonary disease of compounds of formula (I) wherein the C(=NH)-NHR3 group may be in tautomeric or isomeric form, or a pharmaceutically acceptable salt thereof, in which: R1 is amino which is mono- or disubstituted by a substitutent selected from an aliphatic hydrocarbon radical, an araliphatic hydrocarbon radical, an aromatic radical, and a cycloaliphatic hydrocarbon radical or is amino which is disubstituted by a divalent aliphatic hydrocarbon radical or a said radical interrupted by oxygen; R2 is hydrogen, halogen, trifluoromethyl, an aliphatic hydrocarbon radical, hydroxy or is hydroxy which is etherified by an aliphatic, araliphatic or aromatic alcohol or by an aliphatic alcohol which is substituted by carboxy, by esterified carboxy or by amidated carboxy or which is esterified by an aliphatic or araliphatic carboxylic acid; R3 is hydrogen or an acyl radical which is derived from an organic carbonic acid, an organic carboxylic acid, a sulfonic acid, or a carbamic acid; X1 and X3, independently or one another, are oxygen (-O-) or sulphur (-S-); and X2 is a divalent aliphatic hydrocarbon radical which may be interrupted by an aromatic radical; wherein the phenyl rings of formula (I) may be, independently or one another, further substituted by one or more substituents selected from halogen, trifluoromethyl, an aliphatic hydrocarbon radical, hydroxy, and hydroxy which is etherified by an aliphatic alcohol or which is esterified by an aliphatic or araliphatic carboxylic acid; wherein aryl in the above definitions may be, independently of one another, further substituted by one or more substitutents selected from halogen, trifluoromethyl, an aliphatic hydrocarbon radical, hydroxy, and hydroxy which is ethereified by an aliphatic alcohol or which is esterified by an aliphatic or araliphatic carboxylic acid; wherein a cycloaliphatic hydrocarbon radical may be substituted by an aliphatic radical.

Description

Substituted amidine compounds and their use in the treatment of chronic obstructive pulmonary disease

Technical field

The present invention relates to the use of organic compounds, in particular substituted amidine compounds, in the treatment of chronic obstructive respiratory diseases, in particular chronic obstructive pulmonary disease (COPD), including pulmonary distribution, cystic fibrosis and in particular chronic bronchitis.

BACKGROUND OF THE INVENTION

COPD is one of the main causes of death and incapacity for work in the US and Europe and there is currently no effective treatment to prevent disease progression. The most common cause is cigarette smoke, which leads to chronic bronchitis. About 15% of smokers develop a progressive restriction of air flow, which often leads to lung spreading.

SUMMARY OF THE INVENTION

In one embodiment, the present invention relates to the use of a pharmacologically active compound of formula I

wherein the C (= NH) -NHR ^{3 group} may be in tautomeric or isomeric form, or a pharmaceutically acceptable salt thereof, wherein:

R ¹ is an amino group which is mono- or disubstituted with a substituent selected from the group consisting of an aliphatic hydrocarbon group, an arylaliphatic hydrocarbon group, an aromatic group and a cycloaliphatic hydrocarbon group, or an amino group which is disubstituted by a divalent aliphatic hydrocarbon group or said group ;

R ² is hydrogen, halogen, trifluoromethyl, an aliphatic hydrocarbon radical, hydroxy or hydroxy which is etherified by an aliphatic, araliphatic or aromatic alcohol or by an aliphatic alcohol which is substituted by carboxy, esterified carboxy or amidated carboxy or which is esterified with an aliphatic or arylaliphatic carboxylic acid;

R ³ is a hydrogen atom or an acyl group which is derived from organic derivatives of carbonic acid, organic carboxylic acid, sulfonic acid or carbamic acid;

X ¹ and X ³ are independently oxygen (-O-) or sulfur (-S-); and X ² is a divalent aliphatic hydrocarbon group which may be interrupted by an aromatic group;

wherein the phenyl rings of formula I may independently be further substituted with one or more substituents selected from the group consisting of halogen, trifluoromethyl, aliphatic hydrocarbon, hydroxyl, and hydroxyl that is etherified with an aliphatic alcohol or which is esterified with an aliphatic or an arylaliphatic carboxylic acid;

wherein the aryl group in the definitions above may be independently further substituted by one or more substituents selected from the group consisting of halogen, trifluoromethyl, aliphatic hydrocarbon, hydroxyl and hydroxyl which is etherified with an aliphatic alcohol or which is esterified with an aliphatic or arylaliphatic carboxylic acid;

wherein the cycloaliphatic hydrocarbon group may be substituted with an aliphatic group;

for the preparation of a medicament for the treatment of chronic obstructive pulmonary disease.

In another embodiment, the present invention provides pharmacologically active compounds of formula I and their pharmacologically active salts for use in the treatment of chronic obstructive pulmonary disease.

In another embodiment, the invention provides a method of treating chronic obstructive pulmonary disease, comprising administering to a mammal in need of such treatment an effective amount of a pharmacologically active compound of formula I, or a pharmaceutically acceptable salt thereof, as hereinbefore defined.

Compounds of formula I wherein the C (= NH) -NHR ^{3 group} is in tautomeric or isomeric form have the formula I ¹

(I ¹ ) wherein R ¹ , R ² , R ³ , X ¹ , X ² and X ³ are as previously defined for formula (I).

Since the compounds of formula I contain a basic center, they can form acid addition salts, especially pharmaceutically acceptable salts. These salts are formed, for example, with inorganic acids such as mineral acids such as sulfuric acid, phosphoric acid or hydrohalic acids or with organic carboxylic acids such as alkanecarboxylic acids containing from 1 to 4 carbon atoms in the alkyl moiety which are, for example, unsubstituted or substituted by halogen , for example acetic acid, such as saturated or unsaturated dicarboxylic acids, for example oxalic acid, malonic acid, succinic acid, maleic acid, fumaric acid, phthalic acid or terephthalic acid, such as hydroxycarboxylic acids, for example ascorbic acid, glycolic acid, acid lactic, malic acid, tartaric acid or citric acid such as amino acids, for example aspartic acid or glutamic acid, benzoic acid or with organic sulfonic acids such as al cansulfonic acids containing 1 to 4 carbon atoms or arylsulfonic acids which are unsubstituted or substituted, for example by a halogen atom, for example methanesulfonic acid or toluenesulfonic acid. Preferred salts are formed with hydrochloric acid, methanesulfonic acid and maleic acid, in particular maleic acid.

Unless otherwise stated, the general definitions used in the text have the following meanings:

An aliphatic hydrocarbon group is, for example, a lower alkyl group, a lower alkenyl group and a secondary lower alkynyl group.

An arylaliphatic hydrocarbon group is, for example, an optionally substituted phenylalkyl group containing a lower alkyl group and a secondary phenylalkenyl group containing a lower alkenyl group and a phenylalkinyl group containing a lower alkynyl group.

A cycloaliphatic hydrocarbon group is, for example, a cycloalkyl group and a secondary cycloalkenyl group which is unsubstituted or mono- or polysubstituted, for example disubstituted, with a lower alkyl group.

A divalent aliphatic hydrocarbon group is, for example, a lower alkylene group.

The divalent aliphatic group interrupted by an oxygen atom is, for example, a lower alkylene group interrupted by an oxygen atom, for example an ethylene-O-ethylene group.

A divalent aliphatic hydrocarbon group interrupted by an aromatic group is, for example, an alkylene-phenylene-alkylene group containing lower alkylene groups.

The aliphatic alcohol is, for example, a lower alkanol or lower alkenol, and the arylaliphatic alcohol is, for example, a phenylalkanol containing a lower alkanol group, for example benzyl alcohol.

A hydroxyl group that is etherified with an aliphatic or arylaliphatic alcohol is, for example, a lower alkoxy group or a lower alkenyloxy group and a phenylalkoxy group containing a lower alkoxy group.

A hydroxyl group etherified with an aliphatic alcohol substituted with a carboxyl group, an esterified carboxyl group or an amidated carboxyl group is, for example, a lower alkoxy group substituted with a carboxyl group, a lower alkoxycarbonyl group, an arylalkoxycarbonyl group containing lower alkoxy group, aminocarbonyl alkyl group or mono- or di- .

For example, an aliphatic carboxylic acid is a lower alkanoic or lower alkenoic acid, an arylaliphatic carboxylic acid is, for example, a phenylalkanoic acid containing a lower alkyl group.

A hydroxyl group that is esterified with an aliphatic or arylaliphatic carboxylic acid is, for example, a lower alkanoyloxy group, a lower alkenoyloxy group or a phenylalkanoyloxy group containing a lower alkanoyl group.

An acyl group derived from an organic carboxylic acid is, for example, a lower alkanoyl group, a phenylalkanoyl group containing a lower alkanoyl group, or an unsubstituted or substituted aroyl group such as a benzoyl group, naphthoyl group, indanoyl group or fluorenoyl group or heteroaroyl group such as pyridylcarbones , thienylcarbonyl, pyrrolylcarbonyl, furanylcarbonyl and imidazolylcarbonyl.

An acyl group derived from an organic carbonic acid is, for example, an alkoxycarbonyl group or an alkenyloxycarbonyl group which is in each case unsubstituted or substituted by an aromatic group or is a cycloalkoxycarbonyl group which is unsubstituted or substituted by a lower alkyl group.

An acyl group which is derived from a sulfonic acid is, for example, an alkanesulfonyl group, an arylalkanesulfonyl group, a cycloalkanesulfonyl group or an arylsulfonyl group.

An acyl group which is derived from a carbamic acid is, for example, an aminocarbonyl group which is substituted by an alkyl group, an arylalkyl group or an aryl group.

An aromatic group is, for example, unsubstituted or substituted, for example monosubstituted or polysubstituted, for example disubstituted or secondary trisubstituted carbocyclic aryl such as phenyl, naphthyl, indanyl or fluorenyl, or heterocyclic aryl such as pyridyl, thiyl, thienyl, thienyl, thienyl, thienyl, a furanyl group and an imidazolyl group.

The aryl group is preferably a monocarbocyclic aryl group, preferably an optionally substituted phenyl group, such as a phenyl group or a phenyl group substituted, for example, by a lower alkyl group, a lower alkoxy group, a halogen atom or a trifluoromethyl group.

The phenyl rings of formulas I and I ¹ as well as aromatic radicals referred to before and hereafter are generally unsubstituted or further substituted such as monosubstituted or polysubstituted, for example disubstituted or secondarily trisubstituted, in particular, e.g., substituents selected from, halo, trifluoromethyl, , lower alkyl, lower alkenyl, lower alkynyl, hydroxyl, lower alkoxy, lower alkenyloxy, lower alkoxy-containing phenylalkoxy, lower alkanoyloxy, lower alkenoyloxy, and lower-phenylalkanoyloxy. The phenyl rings of formulas I and I ¹ do not have further substituents.

Preferred positions in the following structural elements on the corresponding phenyl ring of Formula I are: positions 4 (para) or 5 (meta) for the -CO-R ^{1 group} , position 2 (ortho) or 3 (meta) for the R ² group, and position 4 (para) for the group -C (= NH) -NHR ³ and both tautomeric and isomeric forms form part of the present invention.

The term "substituted with one or more substituents" means preferably one, two or three such substituents, preferably one or two.

The term "lower" means that the corresponding groups and compounds in each case contain no more than 7, preferably no more than 4, carbon atoms.

In particular, the halogen atom is a fluorine atom, a chlorine atom or a bromine atom and furthermore includes an iodine atom.

Lower alkyl is especially alkyl having up to 7 carbon atoms, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, and further includes the corresponding pentyl, hexyl and heptyl. An alkyl group having 1 to 4 carbon atoms is preferred.

Lower alkenyl is especially C 3 -C 7 alkenyl, for example 2-propenyl or 1-, 2- or 3-butenyl. C 3 -C 5 alkenyl is preferred.

Lower alkynyl is in particular C3 -C7 alkynyl and is preferably propargyl.

Phenylalkyl having a lower alkyl group is especially phenylalkyl having 1 to 4 carbon atoms in the alkyl moiety and preferably a benzyl group, 1- and 2-phenyl group, whereas a phenylalkenyl group having a lower alkenyl group and a phenylalkinyl group having a lower alkynyl group are especially phenylalkenyl. a C 2 -C 5 alkenyl group and a C 2 -C 5 phenylalkynyl group, in particular a 2-phenylvinyl group, a 3-phenylalyl group and a 3-phenylpropargyl group.

Cycloalkyl is especially cycloalkyl having 3 to 7 carbon atoms, for example cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl. Cyclopentyl and cyclohexyl are preferred.

Cycloalkenyl is especially cycloalkenyl of 3 to 7 carbon atoms and is preferably cyclopent-2-enyl or cyclopent-3-enyl or cyclohex-2-en-yl and cyclohex-3-en-yl.

A lower alkylene group, for example, in an amino group which is disubstituted by a lower alkylene group, is in particular an alkylene group having 2 to 6 carbon atoms and is, for example, a butylene group, a pentylene group or a 2,6-hexylene group. Preferred is an alkylene group having 4 to 5 carbon atoms, in particular a pentylene group.

Lower alkylene X ² is especially C 2 -C 8 alkylene, preferably straight chain, and is, for example, ethylene, propylene, butylene, pentylene, hexylene, heptylene and also octylene. Alkylene having 4 to 7 carbon atoms is preferred, especially pentylene, and also butylene, hexylene or heptylene.

The lower alkylene group which is interrupted by the phenyl group (X ² ) is in particular an alkylene-phenylene-alkylene group containing lower alkylene groups or an alkylene-naphthylene-alkylene group containing lower alkylene groups such as an alkylene-phenylene-alkylene group containing 2 to 4 carbon atoms in each alkylene moiety or an alkylene moiety of 2 to 4 carbon atoms, preferably containing a straight chain, and is, for example, a methylene-phenylene-methylene group, a 1,2-ethylene-phenylene-1,2-ethylene group, such as a 1,2-ethylene-1,4-phenylene-1,2-alkylene moiety -ethylene, 1,3-propylene-phenylene-1,3-propylene, such as 1,3-propylene-1,4-phenylene-1,3-propylene or butylene-phenylene-butylene, also corresponding to 1,2-ethylene-naphthylene-1 , 2-ethylene.

An alkylene-phenylene-alkylene group having 2 to 4 carbon atoms in each alkylene moiety or an alkylene-naphthylene alkylene group having 2 to 3 carbon atoms in each alkylene moiety is particularly preferred, a 1,2-ethylene-1,4-phenylene-1,2-ethylene group.

Lower alkoxy is especially alkoxy having 1 to 7 carbon atoms and is, for example, methoxy, ethoxy, n-propyloxy, isopropyloxy, n-butyloxy, iso10-butyloxy, sec-butyloxy, t-butyloxy, tert-butyloxy, tert-butyloxy, tert-butyloxy.

C 1 -C 4 alkoxy is preferred.

Lower alkenyloxy is especially alkenyloxy having 1 to 7 carbon atoms and is, for example, allyloxy or but-2-enyloxy or but-3-enyloxy. C 3 -C 5 -alkyloxy is preferred.

Phenylalkoxy containing lower alkoxy is especially phenylalkoxy having 1 to 4 carbon atoms in the alkoxy moiety, such as benzyloxy, 1- or 2-phenylethoxy, or 1-, 2- or 3-phenylpropyloxy.

Lower alkanoyloxy is especially alkanoyloxy having 2 to 8 carbon atoms, in particular alkanoyloxy having up to 5 carbon atoms, such as acetyloxy, propionyloxy or pivaloyloxy.

Lower alkenoyloxy is especially C3 -C8 alkenoyloxy, especially alkenoyloxy of up to 5 carbon atoms, such as propenoyloxy.

Phenylalkanoyloxy containing lower alkanoyl is in particular phenylalkanoyloxy containing 2 to 8 carbon atoms, especially phenylalkanoyloxy containing 2 to 5 carbon atoms, such as phenylacetyloxy, phenylpropionyloxy or phenylpropionyloxy.

Alkoxycarbonyl is especially alkoxycarbonyl having 2 to 12 carbon atoms and is, for example, methoxy, ethoxycarbonyl, propyloxycarbonyl, pivaloyloxycarbonyl or octyloxycarbonyl. C 2 -C 9 alkoxycarbonyl is preferred.

An alkenyloxycarbonyl group is in particular an alkenyloxycarbonyl group having 3 to 12 carbon atoms, for example an allyloxycarbonyl group. Preferred is an alkenyloxycarbonyl group having 3 to 5 carbon atoms.

Cycloalkyloxycarbonyl is especially cycloalkyloxycarbonyl having 3 to 7 carbon atoms, cyclopentyloxycarbonyl or cyclohexyloxycarbonyl being preferred.

The alkanesulfonyl group is in particular an alkanesulfonyl group having 1 to 7 carbon atoms and is, for example, methanesulfonyl, ethanesulfonyl, n-propanesulfonyl or isopropanesulfonyl. C 1 -C 4 -alkanesulfonyl is preferred.

Arylalkanesulfonyl is especially phenylalkanesulfonyl having 1 to 7 carbon atoms in the alkane moiety, for example benzyl or 1- and 2-phenylethanesulfonyl. A phenylalkanesulfonyl group containing 1 to 4 carbon atoms in the alkane moiety is preferred.

Cycloalkanesulfonyl is especially cycloalkanesulfonyl having 3 to 7 carbon atoms, cyclopentanesulfonyl or cyclohexanesulfonyl being preferred.

Naphthyl is 1-naphthyl or 2-naphthyl.

An indanyl group is, for example, a 1-, 2-, 3- or 4-indanyl group.

Fluorenyl is, for example, 1-, 2-, 3-, 4- or 5-fluorenyl.

Lower alkanoyl is especially C1 -C7 alkanoyl and is, for example, formyl, acetyl, propionyl, butyryl, isobutyryl or pivavolyl.

C 2 -C 5 -alkanoyl is preferred.

The lower alkanoyl-containing phenylalkanoyl group is, in particular, a phenylalkanoyl group having 2 to 7 carbon atoms in the alkanoyl moiety and is, for example, a phenylacetyl group or a 2- or 3-phenylpropionyl group. A phenylalkanoyl group containing 2 to 4 carbon atoms in the alkanoyl moiety is preferred.

A substituted aroyl group is an aroyl group such as a benzoyl group which is substituted, for example, by a lower alkoxy group, a lower alkyl group, a hydroxyl group, a hydroxymethyl group or an acyloxymethyl group (such as a lower alkanoyloxymethyl group or a benzoyloxymethyl group).

A naphthoyl group is a 1- or 2-naphthoyl group.

Indanoyl is for example 1-, 2-, 3- or 4-inda- noyl group. Fluorenoyl group is a like 1-, 2-, 3-, 4 - or 5-fluorenoyl. Esterified carboxyl the group is preferably lower alkoxy-

a carbonyl group or an arylalkoxycarbonyl group containing a lower alkoxy group.

The amidated carboxyl group is preferably an aminocarbonyl group, a mono- or dialkylaminocarbonyl group containing lower alkyl groups, a (mono-aryl-mono-alkyl) aminocarbonyl group containing a lower alkyl group, a mono- or di (aryl-alkyl) aminocarbonyl group containing a lower alkyl group, or a (mono-aryl-alkyl-mono-alkyl) aminocarbonyl group containing lower alkyl groups.

The present invention preferably relates to the use of a compound of formula I and a pharmaceutically acceptable salt thereof, wherein:

R ¹ is amino which is mono- or disubstituted with a substituent selected from the group consisting of lower alkyl, lower alkenyl, lower alkynyl, phenylalkyl containing lower alkyl, phenylalkenyl containing lower alkenyl, phenylalkinyl containing lower alkynyl , phenyl, naphthyl, indanyl, fluorenyl, cycloalkyl and cycloalkenyl, cycloalkyl and cycloalkenyl, each of which may be unsubstituted or mono- or polysubstituted by a lower alkyl group, or is an amino group which is disubstituted by a lower group an alkylene group;

R ² is hydrogen, halogen, trifluoromethyl, lower alkyl, lower alkenyl, lower alkynyl, hydroxy, lower alkoxy, lower alkenyloxy, phenyl-lower alkoxy, phenoxy, lower alkoxy substituted by carboxy, lower alkoxycarbonyl, an aminocarbonyl group or a mono- or dialkylaminocarbonyl group containing lower alkyl groups, lower alkanoyloxy group, lower alkenoyloxy group or phenylalkanyloxy group;

R ³ is hydrogen, alkoxycarbonyl or alkenyloxycarbonyl, each of which is unsubstituted or substituted by phenyl, naphthyl, indanyl or fluorenyl, or is cycloalkoxycarbonyl which is unsubstituted or mono- or polysubstituted by lower alkyl, it is a lower alkanoyl group or a phenylalkanoyl group containing a lower alkanoyl group, or it is a benzoyl group, a naphthoyl group, an indanoyl group or a fluorenoyl group, or an alkanesulfonyl group having 1 to 7 carbon atoms, a phenylalkanesulfonyl group having 1 to 7 carbon atoms, cycloalkanes C 3 -C 7, or phenylsulfonyl, or an aminocarbonyl substituted with a lower alkyl group, a phenylalkyl group containing a lower alkyl group an upin or phenyl group;

X ¹ and X ³ are independently oxygen or sulfur;

X ² is a lower alkylene group, an alkylene-phenylene-alkylene group containing lower alkylene groups or an alkylene-naphthylene-alkylene group containing lower alkylene groups;

wherein the phenyl rings of the general formulas (I) may be independently substituted by one or more substituents selected from the group consisting of halogen, trifluoromethyl, lower alkyl, lower alkenyl, lower alkynyl, hydroxyl, lower alkoxy, lower alkenyloxy, phenylalkoxy containing lower alkoxy, lower alkanoyloxy, lower alkenoyloxy and phenylalkanoyloxy containing lower alkanoyl;

wherein the aromatic groups in the above definitions may independently be substituted by one or more substituents selected from the group consisting of halogen, trifluoromethyl, lower alkyl, lower alkenyl, lower alkynyl, hydroxyl, lower alkoxy, lower alkenyloxy, a phenylalkoxy group containing a lower alkoxy group, a lower alkanoyloxy group, a lower alkenoyloxy group, and a phenylalkanoyloxy group containing a lower alkanoyl group.

In particular, the present invention relates to the use of the compounds of formula I and their pharmaceutically acceptable salts, wherein:

R ¹ is an amino group which is mono- or disubstituted by a substituent selected from the group consisting of phenyl and carbon atoms, from the group of up to 7 atoms consisting of alkyl carbon, phenylalkyl of 1 to 7 carbon atoms, up to 6 to 6 in the alkyl portion of the cycloalkyl group a C 3 -C 3 cycloalkyl group may be unsubstituted or a 1 to amino mono group which is C 3 to polysubstituted by alkyl carbon atoms, disubstituted or alkylene, or up to carbon atoms;

R ² is a C 1 -C 7 alkoxy group substituted by a carboxyl or alkoxycarbonyl group or a phenylalkoxy group having 1 to 4 carbon atoms in the alkoxy moiety;

is a hydrogen atom, up to 7 carbon atoms, with 1 lower hydroxyl atom

R ³ is a hydrogen atom, a xyl group containing a benzoyl substituted alkoxycarbonyl group of up to 12 carbon atoms, an alkanoyl group of up to 5 carbon atoms, a phenylalkanoyl alkanoyl group of 2 to 5 atoms having a halogen atom, an alkyl group containing an alkoxy group containing 1 alkylcarbonyl group unsubstituted or substituted by alkyl or alkaloxy, is unsubstituted by trifluoromethyl, up to 7 or carbon atoms, or by carbon atoms, cyclo-3 to 6 carbon atoms, from 1 to 7 carbon atoms, or is benzoyl, naphthoyl, ir. danoyl or fluorenoyl, or it is an alkanesulfonyl group having 1 to 7 carbon atoms, a phenylalkanesulfonyl group having 1 to 7 carbon atoms in the alkane moiety, a cycloalkane sulfonyl group having 3 to 7 carbon atoms, or phenyls a phenyl group, or an aminocarbonyl group which is substituted with an alkyl group having 1 to 7 carbon atoms, a phenylalkyl group having 1 to 7 carbon atoms in the alkyl moiety, or a phenyl group;

X ¹ and X ³ are each -O-, or further independently -O- or -S-;

X ² is a C 2 -C 7 alkylene or C 2 -C 4 alkylene-phenylene-alkylene group;

wherein the phenyl rings of formula (I) may be unsubstituted or further independently substituted with one or more substituents selected from the group consisting of halogen, trifluoromethyl, (C 1 -C 7) alkyl and (C 1 -C 7) alkoxy;

wherein the phenyl group in the above substituents is unsubstituted or further independently substituted with one or more substituents selected from the group consisting of halogen, trifluoromethyl, alkyl of 1 to 7 carbon atoms and alkoxy of 1 to 7 carbon atoms.

In particular, the present invention relates to the use of compounds of formula I and their pharmaceutically acceptable salts, wherein the -CO-R ^{1 group} is located at the 4 (para) or 3 or 5 (meta) position of the corresponding phenyl ring relative to the -X ¹ - group; R ² - is located at the 2 (ortho) or 3 (meta) position of the corresponding phenyl ring relative to the -X ¹ - group; and the -C (= NH) -NHR ^{3 group} is located at the 4 (para) position of the corresponding phenyl ring relative to the -X ³ - group.

In particular, the present invention relates to the use of compounds of formula IA (ΙΑ)

wherein the C (= NH) -NHR ^{3 group} may be in tautomeric or isomeric form, and pharmaceutically acceptable salts thereof, wherein:

R ¹ is a dialkylamino group having 1 to 4 carbon atoms in each alkyl moiety, such as diethylamino or diisopropylamino, alkyl (phenyl) amino having 1 to 4 carbon atoms in the alkyl moiety, such as phenylisopropylamino;

alkyl (phenylalkyl) amino having 1 to 4 carbon atoms in each alkyl moiety, such as methylbenzylamino, dicycloalkylamino of 3 to 6 carbon atoms, such as dicyclohexylamino, which is unsubstituted or substituted by C1-4 alkyl, or piperidinyl; substituted with 1 to 4 carbon atoms such as 2-methyl-1-piperidino;

R ² is hydrogen, C 1 -C 4 alkoxy such as methoxy or C 1 -C 4 alkoxy which is substituted by carboxyl, lower alkoxycarbonyl, aminocarbonyl, or mono- or dialkylaminocarbonyl containing lower alkyl groups;

R ³ is hydrogen, alkoxycarbonyl having 1 to 12 carbon atoms in each alkoxy moiety, such as methoxycarbonyl or octyloxycarbonyl, phenylalkoxycarbonyl having 1 to 4 carbon atoms in the alkoxy moiety such as benzyloxycarbonyl, alkanoyl containing 2 to 5 carbon atoms such as acetyl, benzoyl which is unsubstituted or substituted by halogen, trifluoromethyl, alkyl of 1 to 4 carbon atoms or alkoxy of 1 to 4 carbon atoms such as 3,4-dimethoxybenzoyl, cycloalkylcarbonyl a (C 3 -C 6) cycloalkyl group which is unsubstituted or substituted by a (C 1 -C 4) alkyl group such as a 2-isopropyl-5-methylcyclohexylcarbonyl group;

X ¹ and X ³ are -O-;

X ² is a C 4 -C 7 alkylene group such as a pentylene group;

wherein the phenyl rings of formula IA may be unsubstituted or further independently substituted with one or more substituents selected from the group consisting of halogen, trifluoromethyl, C 1 -C 4 alkyl and C 1 -C 4 alkoxy.

In particular, the present invention relates to the use of compounds of formula IA and their pharmaceutically acceptable salts, wherein:

R ¹ is a C 1 -C 4 dialkylamino group such as diethylamino or diisopropylamino, C 1 -C 4 alkyl (phenyl) amino, such as phenyl isopropylamino, C 1 -C 4 alkyl (phenylalkyl) amino, in each alkyl moiety carbon such as methylbenzylamino, dicycloalkylamino having 3 to 6 carbon atoms, such as dicyclohexylamino which is unsubstituted or substituted by C1-C4 alkyl, or 1-piperidino substituted by C1-C4 alkyl, such as 2-carbon atoms, methyl-1-piperidino;

R ² is hydrogen. hydrogen, C 1 -C 4 alkoxy, such as methoxy or C 1 -C 4 alkoxy which is substituted by carboxyl, lower alkoxycarbonyl, aminocarbonyl or mono- or dialkylaminocarbonyl containing 1 to 4 carbon atoms in each alkyl moiety ;

R ³ is a C 1 -C 4 alkanesulfonyl group such as a methanesulfonyl group, an ethanesulfonyl group or an isopropanesulfonyl group, a C 1 -C 4 phenylalkanesulfonyl group such as a benzylsulfonyl group, a C 4 -C 7 cycloalkanesulfonyl group, is cyclohexanesulfonyl, or phenylsulfonyl, or is aminocarbonyl substituted with C 1 -C 4 alkyl, C 1 -C 4 phenylalkyl, or phenyl;

X ¹ and X ³ are -O-;

X ² is an alkylene group having 4 to 7 carbon atoms, such as a pentylene group.

In particular, the invention relates to the use of compounds of formula IA and their pharmaceutically acceptable salts, wherein:

R ¹ is a C 1 -C 4 dialkylamino group such as diethylamino or diisopropylamino, C 1 -C 4 alkyl (phenyl) amino, such as phenyl isopropylamino, C 1 -C 4 alkyl (phenylalkyl) amino, in each alkyl moiety carbon such as methylbenzylamino, dicycloalkylamino having 3 to 6 carbon atoms such as dicyclohexylamino which is unsubstituted or substituted by alkyl having 1 to 4 carbon atoms, or 1-piperidino substituted by alkyl having 1 to 4 carbon atoms

2-methyl-l-piperidino;

R ² is hydrogen, C 1 -C 4 alkoxy, such as methoxy or C 1 -C 4 alkoxy substituted with C 1 -C 4 alkoxycarbonyl, such as ethoxycarbonylmethyl, or aminocarbonyl;

R ³ is hydrogen; or R ³ is a lower alkanoyl group such as an acetyl group;

X ¹ and X ³ are -O-;

X ² is an alkylene group having 4 to 7 carbon atoms, such as a pentylene group.

The invention further relates, in particular, to the use of the compounds of formula IA and their pharmaceutically acceptable salts, wherein:

R ¹ is a dialkylamino group containing 1 to 4 carbon atoms in each alkyl moiety, such as di-isopropylamino;

R ² is hydrogen, C 1 -C 4 alkoxy, such as methoxy or C 1 -C 4 alkoxy substituted with C 1 -C 4 alkoxycarbonyl or aminocarbonyl;

R ³ is C 1 -C 12 alkoxycarbonyl, such as methoxycarbonyl or octyloxycarbonyl, C 1 -C 4 phenylalkoxycarbonyl, such as benzyloxycarbonyl, C 2 -C 5 alkanoyl, is an acetyl group, a benzoyl group which is unsubstituted or substituted by a halogen atom, a trifluoromethyl group, an alkyl group having 1 to 4 carbon atoms or an alkoxy group having 1 to 4 carbon atoms such as

3,4-dimethoxybenzoyl, a cycloalkylcarbonyl group having 3 to 6 carbon atoms in the cycloalkyl moiety which is unsubstituted or substituted by an alkyl group having 1 to 4 carbon atoms, such as 2-isopropyl-5-methylcyclohexycarbonyl;

X ¹ and X ³ are -O-;

X ² is C 4 -C 7 alkylene, especially pentylene.

In particular, the present invention relates to the use of compounds of formula IA and their pharmaceutically acceptable salts, wherein:

R ¹ is a dialkylamino group containing from 1 to 4 carbon atoms in each alkyl moiety, such as diethylamino or di-isopropylamino;

R ² is hydrogen, C 1 -C 4 alkoxy, such as methoxy or C 1 -C 4 alkoxy substituted by C 1 -C 4 alkoxycarbonyl, such as ethoxycarbonyl or aminocarbonyl;

R ³ is hydrogen or C 1 -C 4 alkanoyl such as acetyl;

X ¹ and X ³ are -O-;

X ² is C 4 -C 7 alkylene, especially pentylene.

In particular, the present invention relates to the use of compounds of formula IB

NH

II 3

C-NH-R

R-OC (IB) wherein the C (= NH) -NHR ^{3 group} may be in tautomeric or isomeric form, and pharmaceutically acceptable salts thereof, wherein:

R ¹ is a dialkylamino group having 1 to 4 carbon atoms in each alkyl moiety, such as diethylamino or diisopropylamino, alkyl (phenyl) amino having 1 to 4 carbon atoms in the alkyl moiety, such as phenylisopropylamino, alkyl (phenylalkyl) amino containing in each alkyl moiety 1-4 carbon atoms such as methylbenzylamino, dicycloalkylamino of 3-6 carbon atoms in each cycloalkyl moiety such as dicyclohexylamino which is unsubstituted or substituted by C1-4 alkyl or 1-piperidinyl substituted by 1 to 4 4 carbon atoms such as 2-methyl-1-piperidino;

R ² is a hydroxyl or C 1 -C 4 alkoxy group which is substituted with a carboxyl group, a lower alkoxycarbonyl group, an aminocarbonyl group or a mono- or dialkylaminocarbonyl group containing lower alkyl groups;

R ³ is hydrogen, C 1 -C 12 alkoxycarbonyl, such as methoxycarbonyl or octyloxycarbonyl, C 1 -C 4 phenylalkoxycarbonyl, such as benzyloxycarbonyl, C 2 -C 5 alkanoyl carbon such as acetyl, benzoyl which is unsubstituted or substituted by halogen, trifluoromethyl, alkyl of 1 to 4 carbon atoms or alkoxy of 1 to 4 carbon atoms such as 3,4-dimethoxybenzoyl, cycloalkylcarbonyl having from 3 to 6 carbon atoms in the cycloalkyl moiety which is unsubstituted or substituted by an alkyl group containing 1 to 4 carbon atoms, such as

2-isopropyl-5-methylcyclohexylcarbonyl;

X ¹ and X ³ are -O-;

X ² is an alkylene group having 4 to 7 carbon atoms, such as a pentylene group;

wherein the phenyl rings of formula IB may be unsubstituted or further independently substituted with one or more substituents selected from the group consisting of halogen, trifluoromethyl, C 1 -C 4 alkyl and C 1 -C 4 alkoxy.

In particular, the present invention relates to the use of compounds of formula IB and their pharmaceutically acceptable salts, wherein:

R ¹ is a dialkylamino group having 1 to 4 carbon atoms in each alkyl moiety, such as diethylamino or di-isopropylamino, alkyl (phenyl) amino having 1 to 4 carbon atoms in the alkyl moiety, such as phenylisopropylamino, alkyl (phenylalkyl) amino containing in each C 1-4 alkyl moiety such as methylbenzylamino, dicycloalkylamino of 3 to 6 carbon atoms in each cycloalkyl moiety such as dicyclohexylamino which is unsubstituted or substituted by C 1-4 alkyl, or 1-piperidino (C 1 -C 4) group such as 2-methyl-1-piperidino;

R ² is a hydroxyl or C 1 -C 4 alkoxy group which is substituted by a carboxyl group, a lower alkoxycarbonyl group, an aminocarbonyl group or a mono- or di-alkylaminocarbonyl group containing lower alkyl groups;

R ³ is a C 1 -C 4 alkanesulfonyl group such as a methanesulfonyl group, an ethanesulfonyl group or an isopropanesulfonyl group, a C 1 -C 4 phenylalkanesulfonyl group such as a benzylsulfonyl group, a C 3 -C 7 cycloalkanesulfonyl group, is cyclohexanesulfonyl, or phenylsulfonyl, or is aminocarbonyl substituted with C 1 -C 4 alkyl, C 1 -C 4 phenylalkyl, or phenyl;

X ¹ and X ³ are -O-;

X ² is an alkylene group having 4 to 7 carbon atoms, such as a pentylene group.

In particular, the present invention relates to the use of compounds of formula IB and their pharmaceutically acceptable salts, wherein:

R ¹ is a dialkylamino group having 1 to 4 carbon atoms in each alkyl moiety, such as diethylamino or di-isopropylamino, alkyl (phenyl) amino having 1 to 4 carbon atoms in the alkyl moiety, such as phenylisopropylamino, alkyl (phenylalkyl) amino containing in each C 1-4 alkyl having 1 to 4 carbon atoms, such as methylbenzylamino, dicycloalkylamino having 3 to 6 carbon atoms in each cycloalkyl moiety, such as dicyclohexylamino, which is unsubstituted or substituted with C 1-4 alkyl or 1-piperidino 1-4 carbon atoms such as 2-methyl-1-piperidino;

R ² is a hydroxyl or C 1 -C 4 alkoxy group which is substituted by a C 1 -C 4 alkoxycarbonyl group such as an ethoxycarbonylmethoxy group or an aminocarbonyl group such as a carbamoylmethoxy group;

R ³ is hydrogen; or R ³ is C 2 -C 5 alkanoyl, such as acetyl;

X ¹ and X ³ are -O-;

X ² is an alkylene group having 4 to 7 carbon atoms, such as a pentylene group.

In particular, the present invention relates to the use of compounds of formula IB and pharmaceutically acceptable salts thereof, wherein:

R ¹ is a dialkylamino group containing from 1 to 4 carbon atoms in each alkyl moiety, such as diethylamino or di-isopropylamino;

R ² is OH or alkoxycarbonylmethoxy alkoxy having 1 to 4 carbon atoms, such as ethoxycarbonylmethoxy, or aminokarbonylmetoxyskupina;

R ³ is hydrogen or C 2 -C 5 alkanoyl, such as acetyl;

X ¹ and X ³ are -O-;

X ² is C 4 -C 7 alkylene, especially pentylene.

Specific particularly preferred compounds are those described in WO 94/11341, EP 0518819, US 5451700 and US 5488160, particularly in the examples given in these publications.

In particular, the present invention relates to the use of a compound of formula IA and pharmaceutically acceptable salts thereof, wherein R ¹ is diisopropylamino, R ² is methoxy, R ³ is hydrogen, X ¹ and X ³ are -O- and X ² is pentylene and compounds of formula IB and pharmaceutically acceptable salts thereof, wherein R ¹ is diisopropylamino, R ² is hydroxyl, R ³ is hydrogen, X ¹ and X ³ are -O-, and X ² is a pentylene group, in particular the maleate salts of said compounds.

Compounds of formula I and salts thereof, wherein R ² is a hydroxyl group esterified with an aliphatic alcohol which is substituted with a carboxyl group, an esterified carboxyl group or an amidated carboxyl group, and methods for their preparation are described in International Patent Application WO 94/11341. Other compounds of formula I and their salts and processes for their preparation are described in EP 0518819, US 5451700 and US 5488160.

Compounds of formula IB may also be prepared by catalytic hydrogenation of a compound of formula II

(II) wherein R ¹ , R ² , R ³ , X ¹ , X ² and X ³ are defined for formula IB when reducing the indicated hydroxyimino group to the imino group, for example using palladium on activated carbon as a catalyst, in a mixture of ethanol and of acetic acid. In this process, the compound of formula IB is isolated in the form of acetate, which, if desired, can be converted into a salt other than the maleate or the free compound using known procedures.

Compounds of formula (II) may be prepared according to the procedure described in US Patent No. 5,452,774.

The maleate (2-butenedioate) of the compound of formula IB wherein R ¹ is diisopropylamino, R ² is hydroxyl, R ³ is hydrogen, X ¹ and X ³ are -O- and X ² is pentylene is new. This salt, (Z) -2-butenedioate 4- [5- [4- (aminoiminomethyl) phenoxy] pentoxy] -2-hydroxy-N, N-bis (1-methylethyl) benzamide, may be prepared as described above. later in the examples.

The compounds of formula I may be prepared in the form of possible isomers or mixtures thereof, for example, as substantially pure geometric (cis or trans) isomers, optical isomers (antipodes), racemates, or mixtures thereof.

Any mixture obtained can be separated on the basis of the physicochemical differences of the components into the pure geometric or optical isomers, diastereoisomers, racemates, for example by chromatography and / or fractional crystallization.

Any racemates of the resulting products or intermediates obtained can be resolved by known methods into optical antipodes, for example by resolution of their diastereomeric salts obtained with optically active acids or bases and liberating the optically active acidic or basic compound. Racemic amidines (where R ³ is a hydrogen atom) can thus be resolved into optical antipodes, for example, by fractional crystallization of the salt formed with an optically active acid.

Since there is a close relationship between the free compounds and the compounds in the form of salts, any reference to a compound mentioned in this context also means the corresponding salt, provided that this is possible or appropriate in the circumstances.

The compounds, including their salts, may also be used in the form of hydrates or may contain other solvents used for their crystallization.

The compounds of formula (I) and salts thereof may be administered enterally, for example, orally or rectally, by the pulmonary route, for example, by inhalation, through the skin and parenterally to mammals, including humans, in effective amounts alone or in combination with one or more pharmaceutically acceptable carriers.

The active compound may be administered in a composition comprising, for example, 0.1 to 95%, for example 1 to 80%, 10 to 80%, or preferably 20 to 60%, of the active compound. Examples of pharmaceutical compositions for enteral or parenteral administration are uniform dosage forms such as coated tablets, tablets, capsules or suppositories as well as ampoules. These compositions are prepared by methods known to those skilled in the art, for example using conventional mixing, granulating, coating, dissolving or freeze-drying. Pharmaceutical compositions for oral administration can thus be obtained by mixing the active compound with solid excipients to obtain a mixture which is optionally granulated and the mixture or granules, if necessary or suitable, processed after the addition of suitable ingredients to the tablets or cores of the coated tablets. .

Suitable compositions for enteral or parenteral administration are tablets and gelatin capsules containing the active ingredient together with a) diluents, for example lactose, dextrose, sucrose, mannitol, sorbitol, cellulose and / or glycine; b) lubricants, for example silica, talc, stearic acid, its magnesium or calcium salt and / or polyethylene glycol; for tablets also with c) binders, for example, aluminum magnesium silicate, starch paste, gelatin, tragacanth, methylcellulose, carboxymethylcellulose sodium or polyvinylpyrrolidone; if appropriate with (d) disintegrants, for example starches, agar, alginic acid or its sodium salt or effervescent mixtures; and / or e) absorbents, colorants, flavors and sweeteners. Injectable suspensions are preferably aqueous isotonic solutions or suspensions, and suppositories are preferably prepared from fatty emulsions or suspensions. Said compositions may be sterilized and / or may contain additives such as preservatives, stabilizers, wetting or emulsifying agents, solubilizers, salts for regulating the osmotic pressure and / or buffers. The cores of the coated tablets are provided with suitable or enteric coatings, inter alia, using concentrated sugar solutions which optionally contain gum arabic, talc, polyvinyl pyrrolidone, polyethylene glycol and / or titanium dioxide, lacquer solutions in organic solvents or solvent mixtures suitable for the preparation of enteric coatings, solutions of suitable cellulosic products such as acetylcellulose phthalate or hydroxypropylmethylcellulose phthalate. Dyestuffs or pigments may be added to the tablets or tablet coatings, for example to allow identification or labeling of different doses of the active compound. The compositions may further comprise other therapeutically active agents. Said compositions are prepared by conventional mixing, granulating or coating processes and contain 0.1 to 75%, preferably 1 to 50%, of the active ingredient.

A medicament, i.e. a pharmaceutical composition suitable for pulmonary administration, may comprise a compound of formula I or a pharmaceutically acceptable salt thereof, as hereinbefore defined, optionally in admixture with a pharmaceutically acceptable carrier, when the compound or mixture is in a form suitable for inhalation. For example, the medicament may be in the form of an aerosol, which may be prepared according to known procedures, or in the form of finely divided particles containing, for example, the active ingredient in the form of finely divided particles with a carrier such as finely divided lactose. These medicaments may be administered by means of an inhalation device suitable for inhalable forms, such as devices known to those skilled in the art.

The aerosol formulation suitable for use in the method of the present invention may comprise a compound of Formula I, or a pharmaceutically acceptable salt thereof, in solution or dispersion in a propellant, which may be selected from propellants known to those skilled in the art, such as fluorocarbons. The concentration of active ingredient in the propellant may be up to 5% by weight, for example 0.1 to 5%, 0.1 to 3%, 0.1 to 2%, 0.2 to 2%, 0.5 to 2% or 1% by weight. up to 2% by weight.

The finely divided inhalable medicament may comprise a compound of Formula I or a pharmaceutically acceptable salt thereof alone or together with a finely divided solid carrier such as glucose, lactose, mannitol, sorbitol, ribose, mannose, arabinose, sucrose, galactose, fructose or xylose. In such a medicament, the compound of formula I or a salt thereof suitably has a mean particle size of up to 10 microns, preferably up to 5 microns, in particular up to 3 microns. Suitably at least 70%, preferably at least 80%, of the particles present in such a particulate medicament have a mean particle size of up to 10 microns, preferably up to 5 microns, especially up to 3 microns.

According to the foregoing, the present invention also provides a pharmaceutical composition comprising as an active ingredient a compound of Formula I, or a pharmaceutically acceptable salt thereof, as hereinbefore defined, for use in the treatment of chronic obstructive pulmonary disease.

In conjunction with another active ingredient, the compound of Formula I or a pharmaceutically acceptable salt thereof may be administered either simultaneously, before or after the other active ingredient, either separately by the same or different routes of administration or together in the same pharmaceutical composition.

The dosage of the active compound to be administered depends on the species of warm-blooded animal (mammal), body weight, age and individual condition and on the form of administration. A unit dosage for oral administration to a mammal of about 70 kg may contain, for example, 1 to 1000 mg / kg of active ingredient per day.

The effect of the compounds of formula I or their pharmaceutically acceptable salts in the treatment of chronic obstructive pulmonary disease can be tested in a mouse model of lipopolysaccharide-induced pulmonary neutrophilia via intranasal instillation. Bacterial lipopolysaccharide (LPS) is a bacterial macromolecular cell surface antigen that, when administered in vivo, elicits a network of inflammatory responses. The main characteristics of this model of LPS-induced lung inflammation, macrophage activation, tumor necrosis factor-α (TNF-α) production, and neutrophil infiltration and activation are features of chronic obstructive pulmonary disease. This model causes pulmonary inflammation as an acute injury that occurs for 2-4 hours in the airway lumen when all inflammatory parameters can be assessed by bronchoalveolar lavage (BAL).

Dissolve the test compound in dimethylsulfoxide (DMSO) and add sterile phosphate buffered saline (PBS) (50 μΐ) to the obtained solution. The final DMSO concentration is 2%. Female Balb / C mice (20-25 g) are anesthetized with halothane / oxygen / nitrous oxide intranasally with PBS DMSO solution containing the test compound at the appropriate dose (0.1-30 mg / kg) or diluent alone and after 30 min. administered 0.3 mg / kg LPS (Salmonella Tyfosa, Sigma). The animals are placed in plastic cages in an air-conditioned room at 24 ° C. Water and feed are freely accessible. Three hours after intranasal administration of LPS, the animals are sacrificed with sodium pentobarbitone (60 mg / kg, i.p.), the abdominal cavity is opened and the animals are bled by removal of the main blood vessels.

The trachea is cannulated and bronchoalveolar lavage (BAL) is performed by injecting PBS four times into the lungs through the trachea. The liquid is then immediately collected and the cell suspension is stored on ice. Total cell counts were measured and a cytospin preparation (Shandon Scientific Ltd, Cheshire, UK) was prepared. Cells are stained with Dif-Quick (Baxter Dade AG, Dudingen, Switzerland) and 200 cell differential counts are performed using standard morphological criteria. The rinsing liquids are centrifuged at 1200 rpm for 10 minutes, the supernatant is aliquoted and stored at -80 ° C.

BAL myeloperoxidase (MPO) activity is measured fresh

BAL supernatant using a 96-well colorimetric assay. 50 μΐ of sample (duplicate) is mixed with 100 μΐ of substrate buffer for 5 minutes at room temperature (sodium phosphate 50 mM, pH 6.0, containing 0.5% hexadecyltrimethylammonium bromide, 0.167 nM o-dianisidine dihydrochloride and 0.4 mM hydrogen peroxide) ). The reaction is terminated by the addition of 100 μ% of 5% sodium azide in distilled water and the optical density (OD) is read at 450 nm. Results are expressed as U / ml using a standard curve based on human leukocytmyeloperoxidase (Sigma).

The inhibitory effect of the test compound on pneumonia is demonstrated by reducing the neutrophil count and / or reducing the MPO activity achieved after administration of the compound compared to the activity obtained after administration of the diluent alone.

In a modification of the above procedure, the test compound (or diluent itself for comparison) is intranasally administered a second time at the same dose 6 hours after LPS administration and sacrificed 18 hours after the second administration. A further modification of the above procedure that can be used is described in Goncalves de Moraes et al., 1996 British Journal of Pharmacology, 117, 1792-1796.

DETAILED DESCRIPTION OF THE INVENTION

100.76 g of 4- [5- [4- (amino (hydroxyimino) methyl) phenoxy] pentoxy] -2-hydroxy-N, N-bis (1-methylethyl) benzamide prepared according to the procedure described in US Patent No. 5,455,274, 370 ml of acetic acid and 800 ml of ethanol are gently shaken and heated to 50-52 ° C to give a light yellow solution. 13.2 g of 10% palladium on carbon are added and the mixture is hydrogenated at 50 psi at 52-54 ° C for 24 hours. Filter the hot reaction mixture through diatomaceous earth and wash the filter cake twice with 2: 1 ethanol / acetic acid. The solvents were then evaporated in vacuo at 75 ° C. Toluene (200 ml) was added to the residue and the solvents were removed in vacuo. This procedure was repeated twice to remove traces of acetic acid and ethanol. 10 g of activated carbon and 50 ml of 2-propanol are added to the residue and the mixture is heated to 75 ° C. The suspension is filtered while hot and washed twice with 50 ml of 2-propanol.

4- [5- [4- (Aminoiminomethyl) phenoxy] pentoxy] -2-hydroxy-N, N-bis (1-methylethyl) benzamide monoacetate is crystallized from 2-propanol to give the product, m.p. 197-199 ° C. .

CHN calcd for C 7 H ₃₈ N ₂ O _{3 6} calculated: % C: 64.78 % H: 7.65 % N: 8.40 found: % C: 64,80 % H: 8.10 % N: 8.13

75.24 g of 4- [5- [4- (aminoiminomethyl (phenoxy) pentoxy] -2-hydroxy-N, N-bis (1-methylethyl) benzamide monoacetate is suspended in 550 ml of anhydrous ethanol and the mixture is stirred under a nitrogen atmosphere A solution of 34.82 g of maleic acid in 75 ml of water is heated to 75 ° C and is quickly added to the mixture, 7 g of activated carbon are added and the black suspension is heated to 80 ° C and filtered. The filter cake was washed with ethanol / water (85 mL / 15 mL) and allowed to cool to room temperature overnight The reaction mixture was cooled to 3-5 ° C for 2 hours and (Z) -2- 4- [5- [4- (Aminoiminomethyl) phenoxy] pentoxy] -2-hydroxy-N, N-bis (1-methylethyl) benzamide butenedioate (1: 1) is filtered off as white crystals, m.p. 212 ° C.

• CHN calcd for C ₂ 9H ₃ gN ₃ O ₈ calculated: % C: 62.46 % H: 7.05 % N: 7.54 found: % C: 62.20 % H: 6, 92 % N: 7.38

Ίν & Ηι

Claims (12)

PATENT CLAIMS Use of a pharmacologically active compound of formula (I) wherein the C (= NH) -NHR ^{3 group} may be in tautomeric or isomeric form, or a pharmaceutically acceptable salt thereof, wherein: R ¹ is an amino group which is mono- or disubstituted with a substituent selected from the group consisting of an aliphatic hydrocarbon group, an arylaliphatic hydrocarbon group, an aromatic group and a cycloaliphatic hydrocarbon group or an amino group which is disubstituted by a divalent aliphatic hydrocarbon group or said hydrocarbon group ; R ² is hydrogen, halogen, trifluoromethyl, an aliphatic hydrocarbon radical, hydroxy or hydroxy which is etherified by an aliphatic, araliphatic or aromatic alcohol or by an aliphatic alcohol which is substituted by carboxy, esterified carboxy or amidated carboxy or which is esterified with an aliphatic or arylaliphatic carboxylic acid; R ³ is a hydrogen atom or an acyl group which is derived from organic derivatives of carbonic acid, organic carboxylic acid, sulfonic acid or carbamic acid; X ¹ and X ³ are independently oxygen (-O-) or sulfur (-S-); and X ² is a divalent aliphatic hydrocarbon group which may be interrupted by an aromatic group; wherein the phenyl rings of formula I may independently be further substituted with one or more substituents selected from the group consisting of halogen, trifluoromethyl, aliphatic hydrocarbon, hydroxyl, and hydroxyl that is etherified with an aliphatic alcohol or which is esterified with an aliphatic or an arylaliphatic carboxylic acid; wherein the aryl group in the definitions above may be independently further substituted by one or more substituents selected from the group consisting of halogen, trifluoromethyl, aliphatic hydrocarbon, hydroxyl and hydroxyl which is etherified with an aliphatic alcohol or which is esterified with an aliphatic or arylaliphatic carboxylic acid; wherein the cycloaliphatic hydrocarbon group may be substituted with an aliphatic group; for the preparation of a medicament for the treatment of chronic obstructive pulmonary disease. Use according to claim 1, wherein: R ¹ is an amino group which is mono- or disubstituted with a substituent selected from the group consisting of alkyl having 1 to 7 carbon atoms, phenylalkyl having 1 to 7 carbon atoms in the alkyl moiety, phenyl and cycloalkyl having 3 to 6 carbon atoms a (C 3 -C 6) cycloalkyl group which may be unsubstituted or mono- or polysubstituted with (C 1 -C 7) alkyl group or an amino group which is disubstituted with (C 3 -C 6) alkylene group; R ² is hydrogen, hydroxy, alkoxy obsahu36 to 7 carbon atoms, alkoxy of 1 to 7 atoms substituted by carboxy or alkoxycarbonyl or, phenyl-alkoxy 1 to 4 carbon atoms; R ³ x ¹ X ^{2 having} 1 atoms lower is hydrogen, an alkoxycarbonyl group containing xyl moieties C 1 -C 12 alkanoyl, phenylalkanoyl C 2 -C 5 to 5 C atoms, alkanoyl moiety which is unsubstituted by C 0 -C 3 or is trifluoromethyl, 1 to 7 7-carbon atoms, or containing benzoyl substituted by halogen, alkyl containing 1 alkoxy containing 1 alkylcarbonyl containing unsubstituted or containing 1 to 7 carbon atoms, benzoyl, or fluorenoyl, phonyl carbon, carbon atoms, cyclo3-6 carbon atoms, atoms of up to 7 substituted with an alkyl or naphthoyl group, indanoyl group or an alkanesulfonyl group having 1 to 7 carbon atoms, a phenylalkanesulfus group having 1 to 7 carbon atoms in the alkane moiety, or a phenylsulfonyl group, or aminocarbonyl a group which is substituted by an alkyl group having 1 to 7 carbon atoms, a phenylalkyl group having 1 to 7 carbon atoms in the alkyl moiety or a phenyl group; X ³ are each -O-, or further independently -O- or -S-; is an alkylene group containing an alkylene-phenylene-alkylene group of the new 2 to 4 carbon atoms; (C 2 -C 7) or containing in each alkylphenyl ring generally substituted or further independently of or more substituents selected from a halogen atom, a trifluoromethyl group, wherein the formula unsubstituted by one alkyl group may be substituted with 1 to 7 carbon atoms; and (C 1 -C 7) alkoxy; wherein the phenyl group in the above definitions is unsubstituted or further independently substituted with one or more substituents selected from the group consisting of atom and halogen, trifluoromethyl, alkyl of 1 to 7 carbon atoms and alkoxy of 1 to 7 carbon atoms. Use according to claim 1 or 2, wherein the -CO-R ^{1 group} is located at the 4 (para) or 3 or 5 (meta) position of the corresponding phenyl ring relative to the -X ¹ - group; R ² is located at the 2 (ortho) or 3 (meta) position of the corresponding phenyl ring relative to the -X ¹ - group; and the -C (= NH) -NHR ^{3 group} is located at the 4 (para) position of the corresponding phenyl ring relative to the -X ³ - group. Use according to claim 1, wherein the compound of formula I has the formula IA NH (IA) wherein the group C (= NH) -NHR ³ may be in tautomeric or isomeric form and wherein: R ¹ is a dialkylamino group having 1 to 4 carbon atoms in each alkyl moiety, an alkyl (phenyl) amino group having 1 to 4 carbon atoms in the alkyl moiety, an alkyl (phenylalkyl) amino group having 1 to 4 carbon atoms in each alkyl moiety, a dicycloalkylamino group containing each a (C 3 -C 6) cycloalkyl moiety which is unsubstituted or substituted by a (C 1 -C 4) alkyl group, or a 1-piperidino (C 1 -C 4) alkyl group; R ² is a hydrogen atom, an alkoxy group having 1 to 4 carbon atoms or alkoxy having 1 to 4 carbon atoms which is substituted by carboxy, lower alkoxycarbonyl, aminocarbonyl or mono- or di-lower alkyl; R ³ is hydrogen, C 1 -C 12 alkoxycarbonyl, C 1 -C 4 alkoxycarbonyl, C 2 -C 5 alkanoyl, benzoyl which is unsubstituted or substituted by halogen, trifluoromethyl, C 1 -C 4 alkyl or C 1 -C 4 alkoxy, C 3 -C 3 cycloalkylcarbonyl up to 6 atoms alkyl, which is unsubstituted or substituted alkyl a group containing 1 to 4 carbon alkyl; X ¹ a X ³ are - -0-; X ² is alkylene a group containing from 4 to 10 7 carbon atoms; where phenyl rings in the formula IAs can be unsubstituted or further independently substituted with one or more substituents selected from the group consisting of halogen, trifluoromethyl, C 1 -C 4 alkyl and C 1 -C 4 alkoxy. Use according to claim 4, wherein R ¹ is a dialkylamino group containing from 1 to 4 carbon atoms in each alkyl moiety; R ² is a hydrogen atom, an alkoxy group having 1 to 4 carbon atoms or alkoxy having 1 to 4 carbon atoms substituted by an alkoxycarbonyl group having 1 to 4 carbon atoms or aminocarbonyl; R ³ is hydrogen or C 1 -C 4 alkanoyl; X ¹ and X ³ are -O-; and X ² is an alkenyl group having 4 to 7 carbon atoms. Use according to claim 4, wherein R ¹ is diisopropylamino, R ² is methoxy, R ³ is hydrogen, X ¹ and X ³ are -O- and X ² is pentylene. Use according to claim 1, wherein the compound of the general formula I has the general formula IB NH (IB) wherein the C (= NH) -NHR ^{3 group} may be in tautomeric or isomeric form, and wherein: R ¹ is a dialkylamino group having 1 to 4 carbon atoms in each alkyl moiety, an alkyl (phenyl) amino group having 1 to 4 carbon atoms in the alkyl moiety, an alkyl (phenylalkyl) amino group having 1 to 4 carbon atoms in each alkyl moiety, a dicycloalkylamino group containing each a (C 3 -C 6) cycloalkyl moiety which is unsubstituted or substituted by a (C 1 -C 4) alkyl group, or a 1-piperidino (C 1 -C 4) alkyl group; R ² is a hydroxyl or C 1 -C 4 alkoxy group which is substituted with a carboxyl group, a lower alkoxycarbonyl group, an aminocarbonyl group or a mono- or di-alkylaminocarbonyl group containing lower alkyl groups; R ³ is hydrogen, C 1 -C 12 alkoxycarbonyl, C 1 -C 4 alkoxycarbonyl, C 2 -C 5 alkanoyl, benzoyl unsubstituted or substituted by halogen a trifluoromethyl group, an alkyl group having 1 to 4 carbon atoms, or an alkoxy group having 1 to 4 carbon atoms, a cycloalkylcarbonyl group having 3 to 6 carbon atoms in the cycloalkyl moiety which is unsubstituted or substituted by an alkyl group having 1 to 4 carbon atoms; X ¹ and X ³ are -O-; and X ² is an alkylene group having 4 to 7 carbon atoms; wherein the phenyl rings of formula IB may be unsubstituted or further independently substituted with one or more substituents selected from the group consisting of halogen, trifluoromethyl, C 1 -C 4 alkyl and C 1 -C 4 alkoxy. Use according to claim 7, wherein R ¹ is diisopropylamino, R ² is hydroxyl, R ³ is hydrogen, X ¹ and X ³ are -O and X ² is pentylene. Use according to any one of claims 1 to 8, wherein the disease is chronic bronchitis. A pharmaceutical composition comprising, as an active ingredient, a compound of formula I according to any one of claims 1 to 8, or a pharmaceutically acceptable salt thereof, for use in the treatment of chronic obstructive pulmonary disease. A medicament suitable for pulmonary administration comprising a compound of formula I according to any one of claims 1 to 8, or a pharmaceutically acceptable salt thereof, optionally in admixture with a pharmaceutically acceptable carrier, when the compound or mixture is in inhalable form. . A compound of formula IB according to claim 8 in the form of a maleate.